This invention relates to the use of an mTOR inhibitor in the treatment or inhibition of uterine leiomyoma (fibroids) in a mammal.
mTOR, also known as FKBP12-rapamycin associated protein (FRAP), is a key enzyme in a variety of signal transduction pathways, including cytokine-stimulated cell proliferation, translation of mRNAs for several key proteins that regulate the G1 phase of the cell cycle, and interleukin-2 (IL-2) induced transcription. Inhibition of mTOR leads to the inhibition of the progression of the cell cycle from G1 to S. Rapamycin (commercially available as Sirolimus™), a macrocycline triene antibiotic produced by Streptomyces hygroscopicus, has been identified as a key mTOR inhibitor.
Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) is an ester of rapamycin. The preparation and use of hydroxyesters of rapamycin, including CCI-779, are described in U.S. Pat. Nos. 5,362,718 and 6,277,983. Still another regioselective method for synthesis of CCI-779 is described in U.S. patent application Ser. No. 10/903,062, filed Jul. 30, 2004 (published Feb. 10, 2005 as U.S. Patent Publication No. US 2005-0033046 A1), and its counterpart, International Patent Application No. PCT/US2004/22860 (published Feb. 24, 2005 as International Patent Publication No. WO 2005/016935 A3). CCI-779 has been described as having an in vitro and in vivo activity against a number of tumor cell types. CCI-779 binds to and forms a complex with the cytoplasmic protein FKBP, which inhibits mTOR. It is hypothesized that CCI-779 delays the tire to progression of tumors or time to tumor recurrence. This mechanism of action is more typical of cytostatic rather than cytotoxic agents and is similar to that of sirolimus.
Uterine leiomyoma (fibroids) are benign tumors arising from the myometrium (smooth muscle layer) of the uterus. Leiomyoma are the most common solid pelvic tumor of women and are 2-5 times more likely to occur in black women than white women. Fibroids occur in as many as 75% of reproductive age women, with 25% of these women symptomatic to the point of seeking treatment. Women with symptomatic fibroids suffer from menorrhagia, pelvic pain and pressure, and are more subject to reproductive dysfunction such as infertility or multiple miscarriages.
The primary treatment for patients with fibroids is surgery—either myomectomy for removal of tumor and preservation of childbearing potential, or hysterectomy. Fibroids are the most common indication for hysterectomy and account for approximately 200,000 procedures performed annually in the United States.
Thus, there is a need in the art for more effective methods of treating and inhibiting fibroids.